Vaccines against Strep A - who.int · POST-INFECTIOUS/IMMUNE NON-COMMUNICABLE >150,000 >300,000 ? ?...

Prof Andrew Steer

Group A Streptococcal Research Group, Murdoch Children’s Research Institute, Australia

Prof Jerome Kim

International Vaccine Institute, Seoul, Korea

Geneva June 27th 2018

Vaccines against Strep A

Last year

Key updates

1. Pathogen

2. Disease burden updates

3. Vaccine candidate landscape

4. Global antigen data

5. Controlled infection models

6. Plans for PPC, Roadmap

This year: outline

PART A: Building momentum (Andrew Steer)

1.Pathogen, disease burden, candidates, infection models

2.WHO Resolution on Rheumatic Heart Disease

3.London meeting May 2018

4.WHO Roadmap

5.WHO PPC

PART B: Strep A Vaccine Enterprise (Jerome Kim)

PART A: Building momentum

1. Pathogen Disease burden

Candidates Models

The pathogen

A ubiquitous human pathogen

Tertiary prevention Surgical/medical

Primary prevention Antibiotic treatment

Secondary prevention Antibiotic prophylaxis

Invasive infections

Superficial infections

Pharyngitis Impetigo

Acute Rheumatic Fever

Rheumatic Heart Disease

Heart failure

Chronic renal failure

Glomerulonephritis

Stroke

ACUTE INFECTIONS

POST-INFECTIOUS/IMMUNE

NON-COMMUNICABLE

>150,000

>300,000

?

?

Cellulitis

Accelerated cardiovascular

disease

Renal replacement therapy

?

?

Rheumatic fever and rheumatic heart disease

Infectious disease Immune-mediated disease

Chronic non-communicable disease

33 million PLWRHD



Watkins et al. NEJM 2015


11.5 million DALYs



Watkins et al. NEJM 2015


305,000 deaths p.a.

30-valent vaccine (StreptAnova)

M protein (HVR region)

Jim Dale, PREVENT, USA

Phase 1 complete (awaiting results)

J8 vaccine M protein (C-terminal peptide)

Michael Good, Australia

Phase 1 of reformulated vaccine (planned)

StreptinCor M protein (C-terminal peptide)

Luiza Guilherme, Brazil

Phase 1 (planned)

“Combo” Non-M protein multi-antigen

Novartis/GSK Under development

Vaccine candidates

Infection models: NHP and CHIM

Rammelkamp CH, 1956

Slide courtesy Joshua Osowicki

SC M1-alum

SC alum

pharyngitis no pharyngitis

M1-alum 1 (5%) 18

alum 12 (48%) 13

P = 0.026

VE = 89% (22.9 - 98.4)

M1 GAS 106 CFU

Fox EN et al, 1973

n=19

n=25


N=44

mucosal M1

placebo


mucosal M1 5 (24%) 16

placebo 17 (74%) 6

M1 GAS 106 CFU

n=21

n=23

N=44

Polly SM et al, 1973


P = 0.006

VE = 68% (28.1 – 85.6)


all controls 15 (42%) 21

all vaccinees 15 (31%) 33

all parenteral 9 (45%) 11

all mucosal 6 (21%) 22

SC M3-alum 3 4

mucosal M3 3 9

SC M12-alum 6 7

mucosal M12 3 13

D’ Alessandri R et al, 1978

SC M3-alum

mucosal M3

SC M12-alum

mucosal M12

M3 GAS 106 CFU

controls

M12 GAS 106 CFU

N=84

Pharyngitis No pharyngitis

All vaccinees 21 (24%) 67

All controls 44 (52%) 40

VE = 54% (30.3 - 70.2)

Total study number = 172

We have a proof of concept of vaccine efficacy from CHIM


P = 0.0003

Conclusions from experimental induction of GAS pharyngitis in humans

- Proof of concept of efficacy

- Safe

- Can generate efficacy data for candidate GAS vaccines

- Can be used to explore immune responses to GAS pharyngitis

- May ‘spotlight’ candidate correlates of protection


CONTROLLED HUMAN INFECTION FOR VACCINES AGAINST

STREPTOCOCCUS PYOGENES


Observational sequential dose-escalation inpatient

study aiming to develop a safe controlled human

infection model of GAS pharyngitis in healthy adults,

establishing the dose of emm75 GAS required to

achieve a reproducible attack rate of ≥60% within 5

days of direct oropharyngeal inoculation.


SCREENING 6 DAY INPATIENT ADMISSION 6 MONTH PERIODIC OUTPATIENT FOLLOW-

UP

LEARNING TESTING

Dose escalation Vaccines

Pathogenesis Therapies

Immune response Diagnostics

Correlate(s) of protection

Transmission

PHARYNGITIS

NO PHARYNGITIS


Ideal GAS pharyngitis CHIM strain emm75 GAS

Causes pharyngitis YES Causes skin infection YES

Limited pre-existing immunity 🤞 Uncommon cause of iGAS YES Uncommon cause of ARF and PSGN YES Antibiotic susceptible YES Whole genome sequence available YES Predictable and limited virulence YES Wide array of candidate vaccine antigens YES

Reliable growth in an animal-free medium YES

Not subject to repeated passage YES Suitable for use in animal models YES Compatible with laboratory assays YES

SCREENING 6 DAY INPATIENT ADMISSION 6 MONTH PERIODIC OUTPATIENT FOLLOW-

UP

Microbiology

Proteomics (serum, plasma, saliva)

Cellular immunity (PBMC)

Humoral immunity (serum, saliva)

Mucosal immunity (saliva)

Genomics (DNA): host, GAS, microbiome

Transcriptomics (RNA): host, GAS

2. WHO Resolution on Rheumatic Heart Disease

31 May 2017 25 May 2018

• Member States of the World Health Organization unanimously adopted a “Global Resolution on Rheumatic Fever and Rheumatic Heart Disease”

• The Resolution was co-sponsored by countries from all six WHO regions.

• The government of New Zealand, which led the drafting process to develop the Resolution, stated: ‘the facts and figures are clear’.

• This argument was reinforced by the delegation of Namibia, who noted that the number of people living with RHD around the world was comparable to those living with HIV.

“…vaccines may improve the prospect for a global reduction in incidence

of all syndromes related to group A streptococci, including cellulitis and

sepsis, maternal and infantile morbidity, and of rheumatic heart disease,

and reduce the use of antibiotics for sore throats (an important concern

in the context of growing antimicrobial resistance resulting from

antibiotic exposure).”

“Research:… development of a safe and effective vaccine”

3. London Meeting May 2018

Seoul Meeting, December 2016

Defining the gaps and needs in:

(1) Global GAS epidemiology and diversity, burden of disease

(2) Immunology and pathophysiology

(3) Pre-clinical vaccine development

(4) Clinical vaccine development

(5) Licensure pathway, policy recommendations, commercialization & delivery

WHO IVR Consultation on GAS vaccine R&D 16-17th May 2018

Wellcome Trust, London, UK

• Review the present status of GAS vaccine R&D, and identify bottlenecks

• Build consensus on priority R&D pathways including establishment of proof of concept, safety guards, stage gates, case definitions

• Review evidence gaps related to medical need and potential value of vaccines

• Promote GAS vaccine R&D investments and stakeholder engagement

• Strengthen the institutional framework incl. research capacity in LMICs

• Provide vaccine stakeholders with guidance on priority activities:

– WHO GAS vaccine technical R&D roadmap

– WHO preferred product characteristics

• Promote implementation of the WHO roadmap

Objectives

*

4. WHO Roadmap for Strep A Vaccines

WHO GAS Vaccine Advisory Group draft

Expert stakeholder review of draft

Public Consultation

London meeting

Final document

Strep A Vaccine Roadmap and PPC

Roadmap vision

“A safe, globally effective and affordable GAS vaccine is needed to prevent and potentially eliminate

acute GAS infections (pharyngitis, skin infections, cellulitis, invasive disease)

and associated antibiotic use,

immune-mediated sequelae (kidney disease, rheumatic fever and rheumatic heart disease)

and associated mortality.”

Roadmap goals

Near-term strategic goal: To demonstrate favourable safety and proof of efficacy of a candidate vaccine against GAS pharyngitis and skin infection in children.

Long-term strategic goal: To develop a safe, globally effective and affordable GAS vaccine for prevention of acute infections (pharyngitis, skin infections, cellulitis, invasive disease) and associated antibiotic use, and secondary immune-mediated sequelae (kidney disease, rheumatic fever and rheumatic heart disease) and associated mortality.

Research

Vaccine development

Key capacities

Policy, commercialization, delivery

Research

Global burden of disease estimates and epidemiology

Spectrum of natural disease history, esp. post-infectious diseases

Antibiotic use, and impact of a vaccine on AMR

1

Vaccine development

Antigen discovery – more candidates

Consensus on safety monitoring

Immunological surrogates / correlates of protection

Pivotal clinical trial design (near and long-term goals)

2

Key capacities

Define role of animal models, including NHP

Develop CHIM for early POC

Establish expert research centres in LMICs

Access low-cost cGMP manufacturing

Develop standardardised quality immune assay platforms

3

Policy, commercialization and delivery

Vaccine value proposition – full scope of costs and benefits

Functional, cost-effective immunisation delivery platform

Post-implementation surveillance platforms

4

5. WHO Preferred Product Characteristics

for Strep A Vaccines

Product developme

nt

WHO SAGE

Policy

Licensure

Country interest

WHO PQ

Financing

WHO PPC: bridging development, licensure, policy, financing, use

Informing GAVI Vaccine Investment Strategy

High level requirements: Address a true public health need Favourable value proposition

Implementation

INTRODUCTION I.Background and purpose

II.Public health need for GAS vaccines

III.WHO strategic goals for GAS vaccines

I. Near-term goals II. Long-term goals

IV.Clinical research and development considerations I. Vaccine construct, antigen target II. Target population III. Efficacy evaluation IV. Safety evaluation V. Value proposition

PREFFERRED PRODUCT CHARACTERISTICS: Parameters

Preferred Product Characteristics: parameters

1. Indication 2. Target population for primary immunization 3. Schedule, primary immunization and boosting 4. Efficacy targets 5. Strain and serotype coverage 6. Safety 7. Adjuvant requirement 8. Immunogenicity 9. Non-interference 10. Route of administration 11. Registration, prequalification and programmatic suitability 12. Value proposition

Parameter Preferred Characteristic

Indication Prevention of GAS-related pharyngitis, superficial skin infections, cellulitis, toxin-mediated disease, invasive infections and associated antibiotic use, secondary rheumatic fever, rheumatic heart disease and post-streptococcal glomerulonephritis.

Target population for primary immunization

Primary schedule: infants and/or young children.

Schedule, primary immunization and boosting

No more than three doses required for primary immunization

Efficacy targets Preferences for target efficacy differ according to the severity of the target disease syndrome -80% protection against non-severe, non-invasive, confirmed GAS disease -70% protection against confirmed GAS cellulitis and other invasive infections -50% protection against long term immune-mediated sequelae

Strain and serotype coverage

Efficacy targets are set irrespectively of strain/serotype considerations. The vaccine composition should ensure that a vast majority (preference for at least 90%) of the current disease-causing isolates from the region targeted for use are prevented.

Safety Safety and reactogenicity profile at least as favourable as current WHO-recommended routine vaccines.

Adjuvant requirement Preference for the absence of an adjuvant. Evidence should be generate to justify adjuvant inclusion in the formulation.

Immunogenicity Established correlate/surrogate of protection based on a validated assay measuring immune effector levels/ functionality.

Non-interference Demonstration of favourable safety and immunologic non-interference upon co-administration with recommended other vaccines if used in the same target population.

Route of administration Injectable (IM, ID, or SC) using standard volumes for injection as specified in programmatic suitability for PQ or needle-free delivery.

Registration, prequalification and programmatic suitability

The vaccine should be prequalified according to the process outlined in Procedures for assessing the acceptability, in principle, of vaccines for purchase by United Nations agencies. WHO defined criteria for programmatic suitability of vaccines should be met (Appendix 1).

Value proposition Dosage, regimen and cost of goods amenable to affordable supply. The vaccine should be cost-effective and price should not be a barrier to access including in low and middle income countries.

Near-term strategic goals:

To demonstrate favourable safety and proof of efficacy of a candidate vaccine against GAS pharyngitis and skin infections in children

highly desired / required

required

1. Indication

Tertiary prevention Surgical/medical

VACCINE

Primary prevention Antibiotic treatment

Secondary prevention Antibiotic prophylaxis

Invasive infections

Superficial infections

Pharyngitis Impetigo

Acute Rheumatic Fever

Rheumatic Heart Disease

Heart failure

Chronic renal failure

Glomerulonephritis

Stroke

ACUTE INFECTIONS

POST-INFECTIOUS/IMMUNE

NON-COMMUNICABLE

>150,000

>300,000

?

?

Cellulitis

Accelerated cardiovascular

disease

Renal replacement therapy

?

?

Long-term strategic goals

2. Target population

• Primary schedule: infants and/or young children.

Research Notes:

-Which? Early infancy, or early childhood

-Booster?

-Special circumstances:

• Secondary prevention in subjects at increased risk of RHD

• Immunization of adults at increased risk of cellulitis or severe invasive disease

• Women

• Campaigns for outbreaks

4. Efficacy targets

• Targets differ according to the severity of target disease:

– 80% against non-severe, non-invasive, confirmed GAS disease

– 70% against confirmed GAS cellulitis and other invasive infections

– 50% against long-term immune-mediated sequelae

Research Notes:

•Stage-gate criteria:

• CHIM may be valuable

• Early proof of concept focusing on pharyngitis

• Cellulitis and invasive infections will require larger sample size

• Pilot implementation or post-licensure studies for less frequent endpoints

•Vaccine development informed by epidemiological characterization.

• Comprehensive characterization of causal pathways leading to RHD

• An evidence-based determination of the reduction in RHD to be expected from a vaccine-mediated prevention of pharyngitis would be highly valuable.

5. Strain and serotype coverage

• Vast majority (preference >90%) of the current disease-causing isolates from the region targeted for use are prevented.

55

Research Notes:

•Immune assays to infer strain/serotype specificity of protection.

•The role of variation over time and potential for bacterial population replacement should be characterized

6. Safety

• Safety and reactogenicity profile at least as favourable as current WHO-recommended routine vaccines

56

Research Notes:

•A stage-gate vaccine development strategy should be developed to minimize subject exposure to a vaccine-derived risk of immune sequelae.

•The role of sequence homology analysis, pre-clinical animal models, human tissue reactivity, and human antigen screening should be defined.

•The intensity of safety investigations should be tailored to the amount of accrued evidence about the safety profile.

•Safety endpoints of interest should be protocol defined. The role of special investigations such as echocardiography and autoimmune antibodies should be defined.

12. Value proposition

• Dosage, regimen and cost of goods amenable to affordable supply.

• The vaccine should be cost-effective and price should not be a barrier to access including in LMIC.

58

Research Notes:

• Reduction of antibiotic use in routine practice of high added value.

• The vaccine impact on health systems, economic impact and other aspects of implementation science should be evaluated in large trials, pre- or post-approval, as practicable.

Acknowledgements

Josh Osowicki Kristy Azzopardi Ciara Baker Paul Licciardi

Mark Davies

Jonathan Carapetis

Michael Good

Jim Dale

Pierre Smeesters Hannah Frost

Mark Walker

Nikki Moreland John Fraser

Johan Vekemans David Kaslow Martine Friede

Jerome Kim

PART B: Strep A Vaccine Enterprise (Jerome Kim)

• Dr. Jerome Kim • 27 June 2018

A Strep A Vaccine Enterprise?

Stakeholder Engagement, Collaborative Partnerships, Institutional Framework

Dr Jerome Kim 27 June 2018

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YEAR

Mortality by year (GBD)

HIV

TB

Malaria

S. pneumo u5

RHD

HiB

Rota

typhoid

shigella

GAS mortality is substantial

G-finder Report, 2017

Work in Progress: Spending on Vaccine R&D, 2016

HIV Vaccines $724 M

TB Vaccines $73 M

Shigella Vaccines $18 M

NTS vaccines $0.4 M

Schisto vaccines $2.3 M

GAS vaccines $1.2 M

Minimal current funding for GAS vaccine R&D

Newly Approved Vaccines

• 1/3 of R&D covers new vaccine targets • At least 32 diseases have no vaccines from

companies in review • Cost

$500M less complex vaccine $1 B more complex vaccine

• Failure rate Only 7% of vaccines reaching preclinical

development are licensed Hi Risk, no Incentive – why spend $1 B with a

high risk of failure and a low ROI if successful?

Diseases that don’t make the list of diseases without vaccine R&D •Group A Strep? •Hepatitis E? •Non typhoidal Salmonella? •Shigella?

Diseases without vaccine R&D

Access to Vaccines Index 2017

No major manufacturer has a GAS vaccine program

Do we need another “Initiative, Consortium…”?

Executive Committee

Secretariat

Advocacy R&D Roadmap Teams

Public Health Value Proposition

Investment Case

Business Case

PHVP

Epidemiology

Animal models

CHIMS

Lay

Scientific

Vaccine Mfr

Funders

Policy

A Strep A Vaccine Enterprise (SAVE)?

67

Advocacy

Uptake, Access

Health Economics,

Vaccination

Campaigns

Host Country NRA

Strengthening &

Coordination,

WHO Prequalification

Vaccine

Development

Pathway

Programs

Science Discovery

Epidemiology, Disease Burden Research

Development Delivery

Tech Transfer, Trial Sites,

Project Management,

Trial Execution,

Data Management

Preclinical, Animal,

Toxicology Proof of

Concept,

Process Development

Preclinical 1-3 years

Launch Life cycle

management

Clinical 6-7 years

Registration 1-1.5 years

Vaccine Products

Funding

What makes partnerships successful?

• WHO PPC and R&D Roadmap complete

• There is a World Health Assembly call to action

• Needs ‒ Strep A vaccine consortium

‒ Roadmap driven increases in funding, prioritization, and coordination

‒ Public health value proposition: Business case, Investment case

‒ Manufacturer(s)

‒ End-to-end thinking (integrated product development plan through implementation)

A Consortium is a part of the beginning

• Make the issue known to potential stakeholders

• 1 or more manufacturers / DCVMN

• Commitments to funding GAS vaccine development

• Commitment to advance workstream funding

• FPHVP ‒ Business case ‒ Investment case

Short term goals

Questions and discussion

Vaccines against Strep A - who.int · POST-INFECTIOUS/IMMUNE NON-COMMUNICABLE >150,000 >300,000 ? ?...

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